W11 - Genetics 1 Flashcards
What are the building blocks of genetic code.
What are proteins, what determines their function, and what are their building blocks.
Nucleotides or bases:
Building blocks of the genetic code
- Adenine (A); Cytosine (C); Thymine (T); Guanine (G)
Amino Acids
Building blocks of proteins
- Represented by specific sequence of three bases
- Codons
- Function of a protein is determined by its structure
- Structure of a protein is determined by its sequence of amino acids
How many bases are there in the whole human genome and how many genes code for protein?
Bases:
3 billion bases
Genes that code for protein:
20–25 thousand genes
What is the helix of DNA. What do they carry?
Double-stranded. The two strands carry redundant information.
Each base has a partner on the other strand
- Cytosine pairs with Guanine (C–G)
- Adenine pairs with Thymine (A–T)
How is DNA bundled. What is the human karyotype comprise of?
DNA is bundled in chromosomes
- The human karyotype comprises 46 chromosomes:
- 22 pairs of autosomal chromosomes (1–22)
- Two sex chromosomes (XX or XY)
What determines the structure of protein
Structure of a protein is determined by its sequence of amino acids
What happens when we change a single bases in a codon. What is the caveat
Changing Bases
- Changes the amino acid
- Change structure of protein
- Change function of protein
Caveat
Not necessarily, as each amino acid might has multiple possible codons
What is a single-nucleotide polymorphism (SNP). What are the different bases called?
SNP
- Position on the genome at which the bases (nucleotide) differs between individual
- The two alleles of a SNP are the alternative bases
What determines a person’s genotype at SNP?
Determined by the two alleles on the two copies of the chromosome
What is phenotype. What kinds are there?
Phenotype is the presence, absence or value of a trait of interest
E.g.
- Psychological diagnosis (binary)
- Parenting style (categorical)
- IQ (quantitative)
What are the 5 genetic variants
- SNP
- Insertion–deletion
- Block substitution
- Inversion
- Copy number
Genetic Variant 0
SNP: Single Base differ
Genetic Variant 1
Insertion–deletion variant
- Bases added or missing
Genetic Variant 2
Block substitution
- Multiple bases substituted
Genetic Variant 3
Inversion variant
- Bases replaced with reversed sequence from other strand
Genetic Variant 4
Copy-number variant
- Sequence of bases repeated one or more times
What is the difference between mutation and polymorphism
Mutation:
Rare (<1% allele of population)
Polymorphism:
Common (1%/>1% allele of population)
Male vs Female chromosome. What is the extra step
Female: XX
Male: XY
- In females, to avoid excess X-chromosome protein, one copy of X in each cell is silence/inactivate
- This process is random in all mammals
How does one copy of X get inactivated
- XIST gene
- RNA transcript
- Coats one chromosome to be inactivated as a Barr body
- RNA transcript
- TSIX gene, on other chromosome
- RNA transcript
- Suppresses transcription of XIST
- RNA transcript
- TSIX antisense partner of XIST
- Encoded by same stretch of DNA; transcribed in opposite directions
What is gene equation
P = G + E + GxE + 2cov(G,E)
- P: Phenotype Variance
- G: Geneotype Variance
- E: Environment Variance
- GxE: Variance from gene–environment interactions
- 2cov(G,E): Covariance between genes and environment
What is the heritability equation
h2 = G / P
Therefore, proportion of variance in the phenotype that can be attributed to variance from genes
Define heritability
Heritability is the proportion of the phenotypic variance due to genetic causes
What kind of measurement is heritability based on?
- Local measurement
- Valid for specific population at a specific time
- Depends on the amount of genetic and environmental variation present in the population
- Cannot generalise heritability across populations…
- Valid for specific population at a specific time
Hertiability of some disorders
High
- Autism
- ADHD
- Schizophrenia
- Biopolar
- OCD
Low
- MDD
- Anxiety
- Alcohol
- Eating disorders
*
How do we measure heritability pre-molecular genetics. What fact do we make use of/
Genetic epidemiology
- Related individuals share a predictable amount of genetic material
Example of genetic epidemiology
Twin studies: Concordance rates
- Higher concordnace in MZ (identical genetics) than DZ (half genetics) suggests genetics component
What are models of inheritance
- Dominant vs Recessive
- Autosomal vs X-linked
Dominant vs recessive
Dominant traits
Mutation on one copy of chromosome for expression of the phenotype
Recessive traits
Mutation on both copies (or only copy) of the chromosome
Autosomal vs X-linked*
- Autosomal traits are carried on the autosomal chromosomes (1–22)
- X-linked traits are carried on the X chromosome
How can we infer modes of inheritance
Modes of inheritance can be inferred from a pedigree chart
- Black = Affected
- White = Unaffected
- Circle = Female
- Square = Male
- Slash = Deceased
Pedigree Chart Reading
See Picture
Main Ideas
Dominant
- Cannot skip
- 2 Unaffected Parents cannot have affected offspring
Recessive
- Can skip
- 2 Affected parents cannot have unaffected offspring
X-Linked
- Cannot transfer father to son
- (Recessive) More common in males
- (X-Linked + Dominant) Daughter of affected father must be affected, but father of affected daughter may not be affected
- (X-Linked + Recessive) Father of affected daughter must be affected
What is an example of a mongenic disorder
Fragile-X (Originated from single gene)
What is the gene alteration of fragile-X
Copy-number variant
- in 5′-untranslated region (contains promotor region where transcribing begins) of gene FMR1
- FMR1 essential for synaptic plasticity/learning
- expanded CCG sequence triggers methlyation
- __constricts X chromosome, causing ‘fragile’ appearance
- methyldated promotor region prevents transcription of the gene
What are Polygenic disorders. Are they common?
Many genes with small contribution.
Monogenic disorders (Fragile-X) are the exception to the rule in behavioural and psychiatric genetics: No single gene for schizophrenia, autism, bipolar disorder, depression or anxiety
What does GWAS do
Genome-wide association studies:
- Examine statistical association between a phenotype and many SNP markers throughout the genome
- 500,000 - 2,000,000 markers
What is linkage disequilibrium (LD) and what does it allow us to do. What can chromosomes be thought of
- Association of alleles at different loci in a population is non-random
- __Chromosomes are mosaics (inherited together in chunks), and hence many variants are correlated
- Allows us to observe indirect associations
What is a direct association and indirect association in GWAS
Direct association
- Phenotype has a functional association with a genotyped (measured) SNP
Indirect association
- Phenotype has a functional association with a non-genotyped SNP that is in LD with a genotyped SNP
What is allelic dosage model and allelic association model
Allelic dosage model
Quantitative traits
Is there a statistical association between the phenotypic measurement and the number of copies of the minor allele?
Allelic association model
Categorical and Binary traits
Is one of the two alternative alleles statistically
over-represented in a phenotypic group?
What summarises the results of all GWAS tests of association
Manhattan plot
- Each point represents outcome of test for ONE snp
- x-axis
- Physical location on genome and within a chromosone
- y-axis
- Transformed p value
- Lower p value = higher on axis = stronger association
- x-axis
What are the thresholds for significance in GWAS
Stringent, due to multiple comparisions increasing type 1 error
- a < 5 x 10^-8
- Corresponds to Bonferroni correction for ~1 million independent (uncorrelated) tests
What predicts genotypes at nongenotyped SNPs
Imputation
- Relies on data from a reference panel of individuals genotyped at high density
- Applies patterns of linkage disequilibrium
discovered in the reference panel
What is the term defining “extent to which a sequence is
maintained across species”
Conservation
- High conservation = Important function for evolution
What helps to define the region likely to contain the
functional variant in a SNP (Other than LD)
- Genetic distance
- Recombination rate
- Frequency with which two markers are inherited together
